Protein kinase C showcases allosteric control: activation of LRRK1.

Allosteric regulation of multi-domain protein kinases provides a common mechanism to acutely control kinase activity. Protein kinase C serves as a paradigm for multi-domain proteins whose activity is exquisitely tuned by interdomain conformational changes that keep the enzyme off in the absence of appropriate stimuli, but unleash activity in response to second messenger binding. Allosteric regulation of protein kinase C signaling has been optimized not just for itself: Alessi and colleagues discover that protein kinase C phosphorylates LRRK1, a kinase with even more domains, at sites on its CORB GTPase domain to allosterically activate LRRK1.

PHLPPing the balance: restoration of protein kinase C in cancer.

Protein kinase signalling, which transduces external messages to mediate cellular growth and metabolism, is frequently deregulated in human disease, and specifically in cancer. As such, there are 77 kinase inhibitors currently approved for the treatment of human disease by the FDA. Due to their historical association as the receptors for the tumour-promoting phorbol esters, PKC isozymes were initially targeted as oncogenes in cancer.

Rapid and Reversible Knockdown of Endogenously Tagged Endosomal Proteins via an Optimized HaloPROTAC Degrader.

Inducing post-translational protein knockdown is an important approach to probe biology and validate drug targets. An efficient strategy to achieve this involves expression of a protein of interest fused to an exogenous tag, allowing tag-directed chemical degraders to mediate protein ubiquitylation and proteasomal degradation. Here, we combine improved HaloPROTAC degrader probes with CRISPR/Cas9 genome editing technology to trigger rapid degradation of endogenous target proteins.

Mechanism of activation of SGK3 by growth factors via the Class 1 and Class 3 PI3Ks.

Derailment of the PI3K-AGC protein kinase signalling network contributes to many human diseases including cancer. Recent work has revealed that the poorly studied AGC kinase family member, SGK3, promotes resistance to cancer therapies that target the Class 1 PI3K pathway, by substituting for loss of Akt kinase activity. SGK3 is recruited and activated at endosomes, by virtue of its phox homology domain binding to PtdIns(3)P.

The NF1 somatic mutational landscape in sporadic human cancers.

Background: Neurofibromatosis type 1 (NF1: Online Mendelian Inheritance in Man (OMIM) #162200) is an autosomal dominantly inherited tumour predisposition syndrome. Heritable constitutional mutations in the NF1 gene result in dysregulation of the RAS/MAPK pathway and are causative of NF1. The major known function of the NF1 gene product neurofibromin is to downregulate RAS.